Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[N:11]=[N:12][C:13]1[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=[C:15]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:14]=1O)([O-])=O.C1C2C(=O)C3C(=CC=CC=3)C=2C=CC=1.[OH-:42].[Na+].N(C1C=CC=CC=1)=NC1C=CC=CC=1.[OH2:58]>C(O)(C)C>[OH:42][C:14]1[C:15]([C:23]([CH3:26])([CH3:24])[CH3:25])=[CH:16][C:17]([C:19]([CH3:22])([CH3:20])[CH3:21])=[CH:18][C:13]=1[N:12]1[N+:11]([O-:58])=[C:5]2[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:4]2=[N:1]1
Reactant: [OH-]
Reactant: O
Reactant: CC(C)(C)c1cc(N=Nc2ccc(Cl)cc2[N+](=O)[O-])c(O)c(C(C)(C)C)c1
Agent: O=C1c2ccccc2-c2ccccc21
Agent: [Na+]
Agent: c1ccc(N=Nc2ccccc2)cc1
Solvent: CC(C)O
Product: CC(C)(C)c1cc(-n2nc3cc(Cl)ccc3[n+]2[O-])c(O)c(C(C)(C)C)c1

Procedure:
2-nitro-4-chloro-2'-hydroxy-3',5'-di-t-butylazobenzene 26.0 g and 9-fluorenone 2.0 g were added to a mixture of isopropyl alcohol 80 g, water 14 g and 97% sodium hydroxide 11.0 g, and the resultant mixture was stirred at the boiling point of 79° C. for 8 hours to effect reaction, thus almost all of the azobenzene having disappeared to produce 2-(2-hydroxy-3,5-di-t-butylphenyl)-5-chlorobenzotriazole-N-oxide. Thus, the reaction of Process (b) was completed.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[OH:11].[N:12]#[C:13]Br.CCOCC.[N-:20]=[N+:21]=[N-:22].[Na+]>O.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[O:11][C:13]1[NH:12][N:22]=[N:21][N:20]=1
Reactant: COc1cccc(O)c1OC
Reactant: N#CBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cccc(Oc2nnn[nH]2)c1OC

Procedure:
To a stirred mixture of 50 g. of 2,3-dimethoxyphenol, 35 g. of cyanogen bromide and 300 ml. of ether, maintained at 10°-15° C., 47 ml. of triethylamine was added dropwise over a period of 30 minutes. A solution of 25 g. of sodium azide in 100 ml. of water was added rapidly and the mixture was heated under reflux with stirring for an hour.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][C@@H:8]([CH3:11])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].O[N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[O:24]=[C:15]1[C:16]2[C:17](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](=[O:19])[N:14]1[O:10][CH2:9][C@@H:8]([NH:7][C:6](=[O:12])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH3:11]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](CON1C(=O)c2ccccc2C1=O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 100.2 %

Procedure:
To a mixture of tert-butyl[(1S)-2-hydroxy-1-methylethyl]carbamate 57 (4.03 g, 23.0 mmol), N-hydroxyphthalimide (5.63 g, 34.5 mmol) and triphenylphosphine (9.05 g, 34.5 mmol) in anhydrous THF (172 mL) at 0° C. under nitrogen was added DIAD (6.69 mL, 34.5 mmol) in anhydrous THF (40 mL) over 15 minutes. The mixture was stirred at 0° C. for 30 min and at room temperature for 2.5 h. Solvent was evaporated off and the residue was subjected to chromatography to give a white solid 58 (7.38 g).
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[CH:22]=[C:21]([Br:23])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1[O:24][CH3:25].CN(C)[CH:28]=[O:29].[Cl-].[NH4+]>C1COCC1>[Br:23][C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([O:24][CH3:25])=[C:13]([CH:28]=[O:29])[CH:22]=1
Reactant: COc1c(Br)cc(Br)c2ccccc12
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1c(C=O)cc(Br)c2ccccc12
Reaction time: 0.5 h
Yield: 15.1 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (1.6 M, 56.9 ml, 91.1 mmol) was added dropwise to a solution of 2,4-dibromo-1-methoxy-naphthalene (30.3 g, 95.9 mmol) in THF (1,800 ml) at −78° C. and the reaction mixture was stirred at the same temperature for 30 minutes. To this mixture, N,N-dimethylformamide (8.9 ml, 115.1 mmol) was added at −78° C. The mixture was stirred at the same temperature for three hours, and then a saturated ammonium chloride aqueous solution was added thereto and the mixture was extracted with ether. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:8)] to obtain the title compound (3.85 g, 15%).
Reaction SMILES: [OH-].[K+:2].C[O:4][C:5]([C:7]1[CH:8]=[C:9]([C:17]#[C:18]C(C)CO)[CH:10]=[C:11]([C:13]([O:15]C)=[O:14])[CH:12]=1)=[O:6]>C(O)CCC>[C:17]([C:9]1[CH:10]=[C:11]([C:13]([O-:15])=[O:14])[CH:12]=[C:7]([CH:8]=1)[C:5]([O-:6])=[O:4])#[CH:18].[K+:2].[K+:2]
Reactant: COC(=O)c1cc(C#CC(C)CO)cc(C(=O)OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: C#Cc1cc(C(=O)[O-])cc(C(=O)[O-])c1
Yield: 97 %

Procedure:
Into a 5 liter four-necked flask equipped with a thermometer, a Dimroth condenser and a stirrer, 3 liters of n-butanol and 182 g (2.763 mole) of potassium hydroxide (85%) were placed and potassium hydroxide was dissolved into n-butanol by heating under the refluxing condition. To the resultant solution, 95 g (0.344 mole) of 4-[3,5-bis(methoxycarbonyl)-phenyl]-2-methyl-3-butyn-1-ol synthesized above in (2) was added and the resultant mixture was heated under the refluxing condition for 30 minutes. The mixture was then cooled in an ice bath. The formed crystals were separated by filtration, washed twice with 1 liter of methanol and dried at 60° C. in vacuo and 88.87 g (the yield: 97%) of dipotassium 5-ethynylisophthalate was obtained.
Reaction SMILES: OCC(C)(C)CCCCC(CCCCC(C)(C)CO)C(O)=O.C[Li].Cl.[OH:26][C:27]([CH:30]([CH2:40][CH2:41][CH2:42][CH2:43][C:44]([CH3:48])([CH3:47])[CH2:45][OH:46])[CH2:31][CH2:32][CH2:33][CH2:34][C:35]([CH3:39])([CH3:38])[CH2:36][OH:37])(C)[CH3:28]>C1COCC1.C(OCC)(=O)C>[OH:46][CH2:45][C:44]([CH3:48])([CH3:47])[CH2:43][CH2:42][CH2:41][CH2:40][CH:30]([CH2:31][CH2:32][CH2:33][CH2:34][C:35]([CH3:39])([CH3:38])[CH2:36][OH:37])[C:27](=[O:26])[CH3:28]
Reactant: CC(C)(CO)CCCCC(CCCCC(C)(C)CO)C(C)(C)O
Agent: CC(C)(CO)CCCCC(CCCCC(C)(C)CO)C(=O)O
Agent: Cl
Agent: [Li]C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)C(CCCCC(C)(C)CO)CCCCC(C)(C)CO
Reaction time: 2 h
Yield: 41 %

Procedure:
8-Hydroxy-2-(6-hydroxy-5,5-dimethyl-hexyl)-7,7-dimethyl-octanoic acid (1.0 g, 3.16 mmol) was dissolved in THF (40 mL) and cooled in an ice-water bath. Methyl lithium (27 mL) was then added at once. The reaction was continued for 2 h at 0 C. The reaction mixture was poured into dilute hydrochloric acid (5 mL concentrated hydrochloric acid in 60 mL water). The organic layer was separated and the aqueous layer was extracted with diethyl ether (2×50 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give the crude product (1.0 g). The crude product was purified by column chromatography (hexanes:ethyl acetate=4:1, then 1:1) to give 9-hydroxy-3-(6-hydroxy-5,5-dimethyl-hexyl)-8,8-dimethyl-nonan-2-one (0.41 g, yield 41%) and 7-(1-hydroxy-1-methylethyl)-2,2,12,12-tetramethyltridecan-1,13-diol (0.4 g, 38%, not shown) as a by-product 1H NMR (300 MHz, CDCl3/TMS): (ppm) 3.46 (s, 4H), 2.65-2.50 (m, 1H), 2.28 (s, 3H), 2.60 (br., 2H), 1.82-1.50 (m, 4H), 1.50-1.25 (m, 12H), 1.02 (s, 12H). 13C NMR (75 MHz, CDCl3/TMS): (ppm) 213.4, 71.7, 53.2, 38.3, 34.9, 31.6, 28.7, 28.3, 23.8. HRMS (LSIMS, nba): Calcd. for C19H39O3 (MH+): 315.2899. found: 315.2866.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=1.C(Cl)(=O)C([Cl:19])=O.ClCCl>O1CCCC1.CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([Cl:19])=[O:12])=[CH:9][CH:8]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(-c2ncccn2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(-c2ncccn2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-pyrimidin-2-ylbenzoic acid of Step A (0.283 g, 1.41 mmol) in dry tetrahydrofuran (20 mL) at room temperature under nitrogen was added N,N-dimethylformamide (1 drop, cat) followed by a 2.0 M solution of oxalyl chloride in dichloromethane (1.41 mmol, 2.82 mmol) and the reaction mixture was stirred at room temperature for 3 hours. The mixture was then concentrated in vacuo to afford 4-pyrimidin-2-yl-benzoyl chloride as a yellow syrup. The crude acid chloride was dissolved in dry tetrahydrof-uran (5 mL), added to a suspension of N-(pyridin-3-ylmethyl)-10,11-dihydro-5Hpyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 76, Step C (0.300 g, 0.942 mmol), and N,N-diisopropylethylamine (0.49 mL, 2.83 mmol) in dry tetrahydrofuran (5 mL), and the reaction mixture stirred at room temperature under nitrogen for 20 hours. The reaction was then quenched by the addition of 2 M sodium hydroxide (10 mL) and the mixture partitioned between ethyl acetate (50 mL) and 2 M sodium hydroxide (50 mL). The organic phase was separated, washed with 2 M sodium hydroxide (2×50 mL), water (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a yellow foam. Purification by flash chromatography using a solvent gradient of 1 to 5% methanol in dichloromethane gave an cream foam that was crystallized from diethyl ether/hexane to afford the title compound (0.395 g, 84%) as white solid, m.p. 234-236° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:10]1(=O)[O:15][C:13](=[O:14])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.O>C(O)(=O)C>[OH:9][C:4]1[CH:3]=[C:2]([N:1]2[C:13](=[O:14])[C:12]3[C:11](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:10]2=[O:15])[CH:7]=[C:6]([CH3:8])[CH:5]=1
Reactant: Cc1cc(N)cc(O)c1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(O)cc(N2C(=O)c3ccccc3C2=O)c1
Yield: 80.6 %

Procedure:
36.0 g (292 mmol) 3-amino-5-methylphenol and 73.5 g (496 mmol) phthalic acid anhydride were heated for 2 h to boiling under reflux in 280 ml glacial acetic acid. Water was added, it was heated for a short time, allowed to cool and filtered. 59.6 g (80%) 2-(3-hydroxy-5-methyl-phenyl)-isoindole-1,3-dione of Fp 174°-175° C. was obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:8]=O.[CH3:10][C:11]1[CH:15]=[C:14]([CH3:16])[NH:13][C:12]=1[CH:17]=[C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][C:19]1=[O:27]>CO>[CH3:10][C:11]1[CH:15]=[C:14]([CH3:16])[NH:13][C:12]=1/[CH:17]=[C:18]1\[C:19](=[O:27])[N:20]([CH2:1][N:2]2[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]2)[C:21]2[CH:26]\1[CH2:25][CH:24]=[CH:23][CH:22]=2
Reactant: C=O
Reactant: CN1CCNCC1
Reactant: Cc1cc(C)c(C=C2C(=O)Nc3ccccc32)[nH]1
Solvent: CO
Product: Cc1cc(C)c(/C=C2\C(=O)N(CN3CCN(C)CC3)C3=CC=CCC32)[nH]1
Temperature: 60 °C
Yield: 67.5 %

Procedure:
N-Methylpiperazine (10 g, 100 mmol) was added to a stirred solution of aqueous formaldehyde (10 g of 38% solution, 100 mmol) and 3-(3,5-dimethyl-1H-pyrrol-2-ylmethylidene)-1,3-dihydro-indol-2-one, (2.38 g, 10 mmol) in methanol (100 mL). The solution heated at 60° C. for 1 h, concentrated to a low volume and the precipitate was filtered off, washed with methanol, and dried to give 2.38 g of the title compound, mp 160-164° C. HPLC Rt 4.72 min. 1H NMR (CDCl3) δ 2.26 (s, 3H), 2.33 (s, 3H), 2.38 (s, 3H), 2.43 (br s, 4H), 2.70 (br s, 4H), 4.59 (s, 2H), 5.96 (d, 1H), 7.02-7.08 (m, 2H), 7.15 (dd, 1H), 7.38 (s, 1H), 7.48 (dd, 1H) and 13.0 (br s, 1H). Anal. Calcd for C21H26N4O: C, 71.97; H, 7.48; N, 15.99. Found: C, 71.75; H, 7.46; N, 15.87.
Reaction SMILES: Br[C:2]1[C:3]([CH2:14][P:15]([OH:18])([OH:17])=[O:16])=[N:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([OH:13])=[O:12])[N:10]=2)[CH:7]=1.[OH-].[Na+]>[Pd].O>[P:15]([CH2:14][C:3]1[CH:2]=[CH:7][N:6]2[CH:8]=[C:9]([C:11]([OH:13])=[O:12])[N:10]=[C:5]2[N:4]=1)([OH:17])([OH:18])=[O:16]
Reactant: O=C(O)c1cn2cc(Br)c(CP(=O)(O)O)nc2n1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cn2ccc(CP(=O)(O)O)nc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-Bromo-7-phosphonomethyl-imidazo[1,2-a]pyrimidine-2-carboxylic acid 19 (15 mg) was introduced in a 250 mL Parr bottle with 0.5N NaOH (1 mL), water (15 mL) and Pd on Carbon (5%, 20 mg). The bottle was evacuated, filled with hydrogen and shaken for one hour at room temperature. The product was purified by passing through a strongly basic ion-exchange column. The product 20 was eluted with 1N HCl.
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([NH:16]C(=O)C)=[C:12]([N+:20]([O-:22])=[O:21])[CH:11]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.Cl.[OH-].[NH4+]>>[N:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([N+:20]([O-:22])=[O:21])[CH:11]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCCC(c1ccc(NC(C)=O)c([N+](=O)[O-])c1)n1ccnc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: CCCC(c1ccc(N)c([N+](=O)[O-])c1)n1ccnc1
Reaction time: 3 h
Yield: 88.9 %

Procedure:
A mixture of 11.5 parts of intermediate 9, namely N-[4-[1-(1H-imidazol-1-yl)butyl]-2-nitrophenyl]acetamide and 150 parts of a hydrochloric acid solution 3N was stirred for 3 hours at reflux temperature. The reaction mixture was poured into crushed ice and the whole was neutralized with concentrated ammonium hydroxide. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated, yielding 8.8 parts (88.9%) of 4-[1-(1H-imidazol-1-yl)butyl]-2-nitrobenzenamine as a residue (interm. 10).
Reaction SMILES: [Br:1]/[CH:2]=[C:3]1/[C@H:4]2[C@:8]([CH3:12])([CH2:9][CH2:10][CH2:11]/1)/[C:7](=[CH:13]/[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)/[C:6](=[O:21])[CH2:5]2.[C:22](Cl)(=[O:24])[CH3:23].N1C=CC=[CH:28][CH:27]=1>>[Br:1]/[CH:2]=[C:3]1\[CH2:11][CH2:10][CH2:9][C@@:8]2([CH3:12])[C@H:4]\1[CH2:5][C:6](=[O:21])/[C:7]/2=[CH:13]\[N:14]([CH2:15][CH2:16][C:17]1[CH:28]=[CH:27][CH:20]=[CH:19][CH:18]=1)[C:22](=[O:24])[CH3:23]
Reactant: C[C@]12CCC/C(=C\Br)[C@@H]1CC(=O)/C2=C\Nc1ccccc1
Reactant: CC(=O)Cl
Reactant: c1ccncc1
Product: CC(=O)N(/C=C1\C(=O)C[C@H]2/C(=C/Br)CCC[C@]12C)CCc1ccccc1
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution of (1Z,3aR,4E,7aS)-4-(bromomethylene)-hexahydro-7a-methyl-1-{(phenylamino)methylene}-1H-indene-2(3H)-one (Compound 27: 182 mg, 0.486 mmol) in pyridine (1 ml), acetyl chloride (50 μl, 0.703 mmol) was added at 0° C. The resulting mixture was allowed to rise to room temperature and stirred for 30 minutes. The solvent was removed by evaporator, and the residue was dissolved in diethyl ether. The resulting mixture was washed with 2 N hydrochloric acid, water and with saturated brine, and dried over magnesium sulfate, followed by evaporation under reduced pressure to obtain a crude product of N-[(1Z)-{(E,3aS,7aR)-7-(bromomethylene)-octahydro-3a-methyl-2-oxoindene-3-ylidene}methyl]-N-phenethylacetamide (184 mg, 91%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([F:12])[CH:11]=1)[C:5](=O)[CH2:6][Br:7].Cl.[NH2:14][OH:15].O>CO>[Br:7][CH2:6][C:5]([C:4]1[CH:3]=[C:2]([F:1])[CH:11]=[C:10]([F:12])[CH:9]=1)=[N:14][OH:15]
Reactant: O=C(CBr)c1cc(F)cc(F)c1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: O
Product: ON=C(CBr)c1cc(F)cc(F)c1

Procedure:
34.5 g (146.8 mmol) 3,5-difluorophenacylbromide, 30.6 g (440.4 mmol) hydroxylamine-hydrochloride, 44.0 ml of water and 320.0 mL methanol were stirred overnight at RT. The reaction mixture was concentrated by rotary evaporation using the rotary evaporator and mixed with 150 mL water and extracted twice with ethyl acetate. The combined organic phases were washed with water, dried and evaporated to dryness by rotary evaporation.
Reaction SMILES: [C:1]([CH:5]1[C:10](=[O:11])[CH2:9][CH:8]([C:12]([S:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)([CH3:14])[CH3:13])[CH2:7][C:6]1=[O:23])(=O)[CH2:2][CH3:3].[CH2:24]([O:27][NH2:28])[CH:25]=C.C1C=CC=CC=1>C(O)C>[CH2:24]([O:27][NH:28][C:1](=[C:5]1[C:10](=[O:11])[CH2:9][CH:8]([C:12]([S:15][C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)([CH3:14])[CH3:13])[CH2:7][C:6]1=[O:23])[CH2:2][CH3:3])[CH3:25]
Reactant: C=CCON
Reactant: CCC(=O)C1C(=O)CC(C(C)(C)Sc2ccc(C)cc2)CC1=O
Solvent: CCO
Solvent: c1ccccc1
Product: CCONC(CC)=C1C(=O)CC(C(C)(C)Sc2ccc(C)cc2)CC1=O
Yield: 68.1 %

Procedure:
1.3 g of 2-propionyl-5-[1-(p-tolylthio)isopropyl]cyclohexane-1,3-dione was allowed to react with 0.3 g of allyloxyamine at room temperature for 15 hours in the mixture of 10 ml of benzene and 3 ml of ethanol. After completion of the reaction, the resulting reaction solution was treated as in Example 1 to obtain 1 g of the desired compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][C:3]=1[N+:24]([O-])=O.[CH:27]1([C:30](O)=[O:31])[CH2:29][CH2:28]1.C(N(CC)C(C)C)(C)C.P(Cl)(Cl)(Cl)=O>ClCCl>[CH:27]1([C:30]([NH:24][C:3]2[CH:4]=[C:5]([CH:8]3[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=4)[NH:9]3)[CH:6]=[CH:7][C:2]=2[F:1])=[O:31])[CH2:29][CH2:28]1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c([N+](=O)[O-])c1)N2
Reactant: O=C(O)C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c(NC(=O)C3CC3)c1)N2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 88.3 %

Procedure:
To an ice-cold mixture of methyl 2-(4-fluoro-3-nitrophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (0.3 mmol, 1.0 eq.), cyclopropanecarboxylic acid (0.46 mmol, 1.5 eq.), N,N-diisopropylethylamine (0.6 mmol, 2.0 eq.) in dichloromethane (5 mL) was added a solution of phosphorus oxychloride (0.36 mmol, 1.2 eq.). Then the reaction mixture was stirred at room temperature for 2.5 hours. LC-MS indicated that the starting material was consumed completely. The reaction was quenched by 20 mL water extracted with ethyl acetate (20 mL×2). The combined organic layer was concentrated and the residue was purified by column chromatography (petroleum ether/ethyl acetate=3:1) to afford 105 mg of methyl 2-(3-(cyclopropanecarboxamido)-4-fluorophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a pale yellow solid; yield: 89%. MS (ESI+APCI) M+1=397.2.
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])=[C:2]=[S:3].[CH3:14][N:15]([CH3:17])[NH2:16]>C(O)C>[CH3:14][N:15]([CH3:17])[NH:16][C:2](=[S:3])[NH:1][C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: CN(C)N
Reactant: COC(=O)c1ccccc1N=C=S
Solvent: CCO
Product: COC(=O)c1ccccc1NC(=S)NN(C)C

Procedure:
A solution of methyl 2-isothiocyanatobenzoate (6.0 g, prepared as described in J. Org. Chem., 1962, 27, 3701) and N,N-dimethylhydrazine (6 ml) in ethanol (60 ml) was stirred at room temperature for 1 hour. The precipitate was filtered off and dried to give methyl 2(3'-dimethylaminothioureido)benzoate (6.73 g, m.p. 149°-152°).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:6]([O:18][CH3:19])[CH:5]=1.Cl.NO.C([N:34](CC)CC)C>C(O)C.C(OCC)(=O)C.O>[NH2:1][CH2:2][CH:3]([NH:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]([NH2:34])=[NH:26])=[CH:23][CH:22]=1)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:6]([O:18][CH3:19])[CH:5]=1
Reactant: CCN(CC)CC
Reactant: COc1cc(C(CN)Nc2ccc(C#N)cc2)ccc1OCc1ccccc1
Agent: Cl
Agent: NO
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: COc1cc(C(CN)Nc2ccc(C(=N)N)cc2)ccc1OCc1ccccc1
Temperature: 67.5 °C
Reaction time: 2 h

Procedure:
4-[2-Amino-1-(4-benzyloxy-3-methoxy-phenyl)-ethylamino]-benzonitrile D (300 mg, 0.8 mmoles) was dissolved in ethanol (3 ml) and hydroxylamine-hydrochloride (350 mg, 5 mmoles) and triethylamine (1 ml, 5.7 mmoles) were added. The reaction was heated to 65-70 degrees C. for 2 hours. The residue was taken up in ethyl acetate and water. The organic layer was separated, dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo and replaced with 4 ml methanol with 0.5 ml acetic acid. Raney nickel (ca. 300 ul suspension in sodium hydroxide, Aldrich) was added and the reaction placed under a hydrogen atmosphere. The reaction was stirred vigorously for 3 hours, the catalyst filtered off and the solvent removed in vacuo. The crude product was purified by flash chromatography on silica gel (ethyl acetate:acetone:methanol:ammonia, 2:1:1:0.05) to yield 160 mgs of 4-[2-Amino-1-(4-benzyloxy-3-methoxy-phenyl)-ethylamino]-benzamidine E. MS (M+H)=391.
Reaction SMILES: [C:1]([C:4]1[C:9]([Cl:10])=[N:8][C:7]([Cl:11])=[CH:6][N:5]=1)([OH:3])=[O:2].[C:12](=O)([O-])O.[Na+].CI.CN(C)C=O>C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH3:12][O:2][C:1]([C:4]1[C:9]([Cl:10])=[N:8][C:7]([Cl:11])=[CH:6][N:5]=1)=[O:3]
Reactant: O=C([O-])O
Reactant: O=C(O)c1ncc(Cl)nc1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ncc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 2-carboxy-3,5-dichloropyrazine (prepared in the above (1)) 226 mg, sodium hydrogen carbonate 118 mg, methyl iodide 0.5 ml and dimethylformamide 1.8 ml is stirred at room temperature for 14 hours. The mixture is diluted with a 10% aqueous citric acid solution and extracted with ethyl acetate. The combined organic layer is washed with water and an aqueous saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to give 2-methoxycarbonyl-3,5-dichloropyrazine as a pale brown crystalline powder 245 mg. mp 60–63° C., MS(m/z): 206(M+)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21](Br)=[C:20](CN(C(OC(C)(C)C)=O)C)[CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:35]([O:39][C:40]([N:42]1[CH2:46][CH2:45][CH2:44][CH:43]1[C:47]1[NH:48][C:49]([C:52]2[CH:57]=[CH:56][C:55](B3OC(C)(C)C(C)(C)O3)=[C:54](C(OC)=O)[CH:53]=2)=[CH:50][N:51]=1)=[O:41])([CH3:38])([CH3:37])[CH3:36].C(=O)(O)[O-].[Na+]>O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:35]([O:39][C:40]([N:42]1[CH2:46][CH2:45][CH2:44][CH:43]1[C:47]1[NH:48][C:49]([C:52]2[CH:57]=[CH:56][C:55]([C:21]3[CH:20]=[CH:19][C:18]([C:15]4[NH:14][C:13]([CH:9]5[CH2:10][CH2:11][CH2:12][N:8]5[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[N:17][CH:16]=4)=[CH:23][CH:22]=3)=[CH:54][CH:53]=2)=[CH:50][N:51]=1)=[O:41])([CH3:38])([CH3:36])[CH3:37]
Reactant: COC(=O)c1cc(-c2cnc(C3CCCN3C(=O)OC(C)(C)C)[nH]2)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: CN(Cc1cc(-c2cnc(C3CCCN3C(=O)OC(C)(C)C)[nH]2)ccc1Br)C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5C(=O)OC(C)(C)C)[nH]4)cc3)cc2)[nH]1
Temperature: 80 °C
Yield: 52.5 %

Procedure:
To the solution of 2-(5-{4-bromo-3-[(tert-butoxycarbonyl-methyl-amino)-methyl]-phenyl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (142 mg, 0.27 mmol) and 2-{5-[3-Methoxycarbonyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (125 mg, 0.25 mmol) in 1,2-dimethoxyether (2.3 ml) and water (0.7 ml) was added sodium bicarbonate (63 mg, 0.75 mmol), followed by Pd(PPh3)4 (12 mg) and PdCl2(dppf)CH2Cl2 (12 mg). The mixture was heated at 80° C. for 20 hours. The mixture was diluted with EtOAc, and was washed with water and brine, and was dried with sodium sulfate. Concentration and purification by flash column chromatography (hexanes/EtOAc) gave 4,4′-bis-[2-(1-tert-butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-biphenyl-2-[(tert-butoxycarbonyl-methyl-amino)-2′-carboxylic acid dimethyl ester (82 mg). m/z: 826 (M+H)+, 413.6 (M+2H)+/2.